The emergence of multi-drug-resistant pathogens has become a serious problem in the chemotherapy of bacterial infectious diseases. One of the strategies that can be used to overcome this problem is to find new bacterial protein targets that provide functions essential for cell growth or replication; and to screen for agents that disrupt in some way that essential function. Another strategy is to improve the efficacy of existing antimicrobial drugs by countering bacterial mechanisms of drug resistance.
As notorious as they may be, bacteria with inherited resistance to antibiotics are not the only reason that antibiotics fail, and may not even be the major reason. Contributing to resistance is the fact that growing populations of bacteria do not just die off when confronted with bactericidal antibiotics. Instead, their rates of mortality decline with time, and viable antibiotic-sensitive cells can be recovered even after hours of exposure to the drug. This phenomenon of declining sensitivity is well established for different species of bacteria and for different classes of antibiotics. Variously called “bacterial persistence”, “phenotypic tolerance”, or “adaptive resistance”, the phenomenon remains a mystery with respect to its mechanism as well as its contribution treatment failure.
One mechanism postulated to account for the declining sensitivity and survival of bacteria confronted with bactericidal antibiotics is that growing populations of genetically identical bacteria continually generate subpopulations that are less sensitive to killing by antibiotics because they either are not growing or are dividing at very low rates.
The ability of bacteria to reduce their susceptibility to antimicrobial drugs importantly affects both bacterial ecology and the treatment of infectious diseases. Previously known mechanisms of bacterial defense against antibiotics include mutation of the drug target, inactivation or destruction of the antimicrobial, and inhibition of antibiotic entry. The present invention addresses the problem of innate susceptibility to antibiotics.